In vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to l-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels

Effects of 5-HT1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats

“…Furthermore, non-DA mediated mechanisms might contribute, including a purported increase in nigral glutamate. 33 Finally, it is important to note that D1R-dependent increases in striatal GAD mRNA found in Experiment 1 did not translate into enhanced nigral GABA here in Experiment 2. However, GAD67 mRNA, which is more strongly associated with LID than GAD65, 28 was not significantly different between acute and chronic SKF81297 administration in the DA-depleted striatum ( Figure 2E).…”

“…However, recent work has indicated that striatal D1/5R, and not D2/3R, antagonism attenuated LID and the concurrent enhancement of nigral GABA. 33 It also appears that striatal D1R stimulation in particular may be responsible, as nigral D1R antagonism did not completely abolish nigral L-DOPA-induced GABA. Furthermore, non-DA mediated mechanisms might contribute, including a purported increase in nigral glutamate.…”

Loss of glutamic acid decarboxylase (Gad67) in striatal neurons expressing the Drdr1a dopamine receptor prevents l-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned mice

“…26 Dopamine Drd1a receptors, which are highly enriched in 27 striatonigral neurons (Le Moine and Bloch, 1995; 28 Surmeier et al, 1996), play a central role in LID. 29 Pharmacological blockade of D1 receptors opposes the 30 dyskinesiogenic effects of L-DOPA in neurotoxin-31 generated experimental models of Parkinson's disease 32 (Monville et al, 2005;Taylor et al, 2005;Westin et al, 33 2007; Murer and Moratalla, 2011;Mela et al, 2012). 34 Consistent with these pharmacological data, genetic inac-35 tivation of dopamine D1 receptors prevents LID (Darmopil 36 et al, 2009).…”

“…34 Consistent with these pharmacological data, genetic inac-35 tivation of dopamine D1 receptors prevents LID (Darmopil 36 et al, 2009). On the other hand, there is evidence that 37 striatal indirect pathway projection neurons (striatopallidal 38 pathway), which preferentially express the dopamine D2 39 and adenosine A2A receptors, are also involved in LID 40 (Svenningsson et al, 1997;Fredduzzi et al, 2002; administration of L-DOPA to dopamine-depleted rodents 48 or monkeys increases gene expression of the GABA-49 synthesizing enzyme glutamic acid decarboxylase (Gad) 50 in striatal neurons (Soghomonian et al, 1996;Cenci 51 et al, 1998) and increases GABA release in the substan-52 tia nigra (Yamamoto et al, 2006;Mela et al, 2007Mela et al, , 2012. 53 In addition, the co-administration of agents that decrease 54 the severity of LID also decreases Gad gene expression 55 in the striatum (Yamamoto and Soghomonian, 2009) or 56 GABA release in the substantia nigra (Mela et al, 2007, (0.1 ml/10 g body weight) immediately following surgery 151 to prevent dehydration and two times a day during the 152 two week recovery period.…”

“…In addition, the co-administration of agents that 452 decrease the severity of LID also decreases Gad67 gene 453 expression in the striatum(Yamamoto and Soghomonian, 454 2009). L-DOPA has been shown to increase the release of 455 GABA in the substantia nigra(Yamamoto et al, 2006; 456 Mela et al, 2007Mela et al, , 2012 and the infusion of a dopamine 457 D1 receptor antagonist into the striatum prevents both 458 the L-DOPA-induced increase in GABA release in the 459 substantia nigra and LID (Mela et al, 2012). In addition, 460 the administration of L-DOPA increases the expression 461 of the vesicular GABA transporter in striatonigral neurons 462…”